Invasive cervical cancers are usually preceded by a long phase of preinvasive disease. This is characterized microscopically as a spectrum of events progressing from cellular atypia to various grades of dysplasia or cervical intraepithelial neoplasia (CIN) before progression to invasive carcinoma. A good knowledge of the etiology, pathophysiology and natural history of CIN provides a strong basis both for visual testing and for colposcopic diagnosis and understanding the principles of treatment of these lesions. This chapter describes the evolution of the classification systems of cervical squamous cell cancer precursors, the cytological and histological basis of their diagnosis, as well as their natural history in terms of regression, persistence and progression rates. It also describes the precancerous lesions arising in the cervical columnar epithelium, commonly referred to as glandular lesions.
The concept of cervical cancer precursors dates back to the late nineteenth century, when areas of non-invasive atypical epithelial changes were recognized in tissue specimens adjacent to invasive cancers ( William, 1888
). The term carcinoma in situ (CIS) was introduced in 1932 to denote those lesions in which the undifferentiated carcinomatous cells involved the full thickness of the epithelium, without disruption of the basement membrane ( Broders, 1932
). The association between CIS and invasive cervical cancer was subsequently reported. The term dysplasia was introduced in the late 1950s to designate the cervical epithelial atypia that is intermediate between the normal epithelium and CIS ( Reagan et al., 19.3
). Dysplasia was further categorized into three groups – mild, moderate and severe – depending on the degree of involvement of the epithelial thickness by the atypical cells. Subsequently, for many years, cervical precancerous lesions were reported using the categories of dysplasia and CIS, and are still widely used in many developing countries.
A system of classification with separate classes for dysplasia and CIS was increasingly perceived as an arbitrary configuration, based upon the findings from a number of follow-up studies involving women with such lesions. It was observed that some cases of dysplasia regressed, some persisted and others progressed to CIS. A direct correlation with progression and histological grade was observed. These observations led to the concept of a single, continuous disease process by which normal epithelium evolves into epithelial precursor lesions and on to invasive cancer. On the basis of the above observations, the term cervical intraepithelial neoplasia (CIN) was introduced in 1968 to denote the whole range of cellular atypia confined to the epithelium. CIN was divided into grades 1, 2 and 3 ( Richart 1968
). CIN 1 corresponded to mild dysplasia, CIN 2 to moderate dysplasia, and CIN 3 corresponded to both severe dysplasia and CIS.
In the 1980s, the pathological changes such as koilocytic or condylomatous atypia associated with human papillomavirus (HPV) infection were increasingly recognized. Koilocytes are atypical cells with a perinuclear cavitation or halo in the cytoplasm indicating the cytopathic changes due to HPV infection. This led to the development of a simplified two-grade histological system. Thus, in 1990, a histopathological terminology based on two grades of disease was proposed: low-grade CIN comprising the abnormalities consistent with koilocytic atypia and CIN 1 lesions and high-grade CIN comprising CIN 2 and 3. The high-grade lesions were considered to be true precursors of invasive cancer ( Richart 1990
In 1988, the US National Cancer Institute convened a workshop to propose a new scheme for reporting cervical cytology results ( NCI workshop report, 1989
; Solomon, 1989
; Kurman et al., 1991
). The recommendations from this workshop and the subsequent revision in a second workshop held in 1991 became known as the Bethesda system (TBS) ( NCI workshop report, 1992
). The main feature of TBS was the creation of the term squamous intraepithelial lesion (SIL), and a two-grade scheme consisting of low-grade (LSIL) and high-grade (HSIL) lesions. TBS classification combines flat condylomatous (HPV) changes and low-grade CIN (CIN 1) into LSIL, while the HSIL encompasses more advanced CIN such as CIN 2 and 3. The term lesion was used to emphasize that any of the morphological changes upon which a diagnosis is based do not necessarily identify a neoplastic process. Though designed for cytological reporting, TBS is also used to report histopathology findings. TBS is predominantly used in North America. The correlation between the dysplasia/carcinoma in situ terminology and the various grades of CIN, as well as TBS, are given in Table 2.1
. We use the CIN terminology in discussing the various grades of cervical squamous precancerous lesions in this manual.
TBS was reevaluated and revised in a 2001 workshop convened by the National Cancer Institute, USA, cosponsored by 44 professional societies representing more than 20 countries ( Solomon et al., 2002
). The reporting categories under the 2001 Bethesda System are summarized in Table 2.2